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When an injured patient arrives in the Emergency Department (ED), timely and appropriate care is crucial. Shock Index Pediatric Age-Adjusted (SIPA) has been shown to accurately identify pediatric patients in need of emergency interventions. However, no study has evaluated SIPA against age-adjusted tachycardia (AT). This study aims to compare SIPA with AT in predicting outcomes such as mortality, severe injury, and the need for emergent intervention in pediatric trauma patients. This is a retrospective cross-sectional analysis of patient data abstracted from the Trauma Quality Improvement Program Participant Use Files (TQIP PUFs) for years 2013–2020. Patients aged 4–16 with blunt mechanism of injury and injury severity score (ISS) > 15 were included. 36,517 children met this criteria. Sensitivity, specificity, overtriage, and undertriage rates were calculated to compare the effectiveness of AT and elevated SIPA as predictors of severe injuries and need for emergent intervention. Emergent interventions included craniotomy, endotracheal intubation, thoracotomy, laparotomy, or chest tube placement within 24 h of arrival. AT classified 59% of patients as “high risk,” while elevated SIPA identified 26%. Compared to AT patients, a greater proportion of patients with elevated SIPA required a blood transfusion within 24 h (22% vs. 12%, respectively; p < 0.001). In-hospital mortality was higher for the elevated SIPA group than AT (10% vs. 5%, respectively; p < 0.001) as well as the need for emergent operative interventions (43% vs. 32% respectively; p < 0.001). Grade 3 or higher liver/spleen lacerations requiring blood transfusion were also more common among elevated SIPA patients than AT patients (8% vs. 4%, respectively; p < 0.001). AT demonstrated greater sensitivity but lower specificity compared to SIPA across all outcomes. AT showed improved overtriage and undertriage rates compared to SIPA, but this is attributed to identifying a large proportion of the sample as “high risk.” AT outperforms SIPA in sensitivity for mortality, injury severity and emergent interventions in pediatric trauma patients while the specificity of SIPA is high across these outcomes.

Here we describe an industry-wide collaboration aimed at assessing the binding properties of a comprehensive panel of monoclonal antibodies (mAbs) against programmed cell death protein 1 (PD-1), an important checkpoint protein in cancer immunotherapy and validated therapeutic target, with well over thirty unique mAbs either in clinical development or market-approved in the United States, the European Union or China. The binding kinetics of the PD-1/mAb interactions were measured by surface plasmon resonance (SPR) using a Carterra LSA instrument and the results were compared to data collected on a Biacore 8K. The effect of chip type on the SPR-derived binding rate constants and affinities were explored and the results compared with solution affinities from Meso Scale Discovery (MSD) and Kinetic Exclusion Assay (KinExA) experiments. When using flat chip types, the LSA and 8K platforms yielded near-identical kinetic rate and affinity constants that matched solution phase values more closely than those produced on 3D-hydrogels. Of the anti-PD-1 mAbs tested, which included a portion of those known to be in clinical development or approved, the affinities spanned from single digit picomolar to nearly 425 nM, challenging the dynamic range of our methods. The LSA instrument was also used to perform epitope binning and ligand competition studies which revealed over ten unique competitive binding profiles within this group of mAbs.

ObjectiveSevere vitamin D deficiency is a recognised cause of skeletal muscle fatigue and myopathy. The aim of this study was to examine whether chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with altered circulating vitamin D metabolites.DesignCohort study.SettingUK university hospital, recruiting from April 2014 to April 2015.ParticipantsNinety-two patients with CFS/ME and 94 age-matched healthy controls (HCs).Main outcome measuresThe presence of a significant association between CFS/ME, fatigue and vitamin D measures.ResultsNo evidence of a deficiency in serum total 25(OH) vitamin D (25(OH)D2 and 25(OH)D3 metabolites) was evident in individuals with CFS/ME. Liquid chromatography tandem mass spectrometry (LC–MS/MS) analysis revealed that total 25(OH)D was significantly higher (p=0.001) in serum of patients with CFS/ME compared with HCs (60.2 and 47.3 nmol/L, respectively). Analysis of food/supplement diaries with WinDiets revealed that the higher total 25(OH) vitamin D concentrations observed in the CFS/ME group were associated with increased vitamin D intake through use of supplements compared with the control group. Analysis of Chalder Fatigue Questionnaire data revealed no association between perceived fatigue and vitamin D levels.ConclusionsLow serum concentrations of total 25(OH)D do not appear to be a contributing factor to the level of fatigue of CFS/ME.

Broadly protective vaccines against known and pre-emergent coronaviruses are urgently needed. Critical to their development is a deeper understanding of cross-neutralizing antibody responses induced by natural human coronavirus (HCoV) infections. Here, we mined the memory B cell repertoire of a convalescent SARS donor and identified 200 SARS-CoV-2 binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of pre-existing memory B cells (MBCs) elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a new target for the rational design of pan-sarbecovirus vaccines.

The majority of metabolomics studies to date have utilised blood serum or plasma, biofluids that do not necessarily address the full range of patient pathologies. Here, correlations between serum metabolites, salivary metabolites and sebum lipids are studied for the first time. 83 COVID-19 positive and negative hospitalised participants provided blood serum alongside saliva and sebum samples for analysis by liquid chromatography mass spectrometry. Widespread alterations to serum-sebum lipid relationships were observed in COVID-19 positive participants versus negative controls. There was also a marked correlation between sebum lipids and the immunostimulatory hormone dehydroepiandrosterone sulphate in the COVID-19 positive cohort. The biofluids analysed herein were also compared in terms of their ability to differentiate COVID-19 positive participants from controls; serum performed best by multivariate analysis (sensitivity and specificity of 0.97), with the dominant changes in triglyceride and bile acid levels, concordant with other studies identifying dyslipidemia as a hallmark of COVID-19 infection. Sebum performed well (sensitivity 0.92; specificity 0.84), with saliva performing worst (sensitivity 0.78; specificity 0.83). These findings show that alterations to skin lipid profiles coincide with dyslipidaemia in serum. The work also signposts the potential for integrated biofluid analyses to provide insight into the whole-body atlas of pathophysiological conditions.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis 1 – 5 . However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance 6 . In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment—which contributes to virologic failure, resistance generation and viral transmission—as well as of pre-exposure prophylaxis, leading to new infections 1 , 2 , 4 , 7 – 9 . Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence 10 . Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log 10 -transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV. The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection.

While the presence of microplastics has been reported in aquatic habitats across the globe, the pathways through which they enter the environment are still poorly understood. Studies investigating the fate of microplastics in wastewater are gaining attention but are still scarce, despite the urgent need to understand the role of wastewater treatment plants (WWTP) as point sources of aquatic microplastic pollution. A likely reason for the limited number of WWTP-associated studies is that working with a biogenic organic matter (BOM)-rich sample matrix like wastewater is challenging. Here, we investigated the presence of microplastics (MP) throughout several stages of a wastewater treatment plant (WWTP) at multiple depths, employing Fenton’s reagent and focal plane array-based reflectance micro-Fourier-transform infrared spectroscopic (FPA-based reflectance micro-FTIR) imaging, a protocol that allows the automated detection and identification of microplastics in complex samples with high organic matter content, without the need for previous visual sorting, or reducing considerably the thickness of the sample, or the use of IR-transparent transmission windows. It was found that the number of microplastic fragments detected at downstream stages of the WWTP notably decreased following the primary settlement stage, with primary settlement stage samples responsible for 76.9% of total microplastics detected. Despite the marked reduction in the number of microplastic particles following the primary settlement stage, an average total of 1.5 MP L-1 were identified in the final effluent of the WWTP.

This paper investigates learning occurring through cross-cultural collaboration and how learning processes and outcomes of such learning affect the governance of regional lands and resources in the context of a First Nation-industry partnership in northwestern Ontario, Canada. We use transformative learning theory as a basis for critically analyzing individual, social, and structural changes. Transformative theory has been found to be suitable for working with natural resource problems and has evolved over time to include ways for accounting for different cultural frames of reference. We attempted a decolonizing approach in our research methodology hoping to understand learning events and outcomes as expressed by the research participants according to their own worldviews. Thirty-six participants involved in the First Nation-industry partnership were engaged in semi-structured interviews. Our results reveal different events that catalyzed both transformative and culturally framed learning outcomes for participants, such as much deeper appreciation for cultural practices and shared understanding of provincial forest policies. Four types of events were identified as catalysts for such learning outcomes: (i) time spent on the land; (ii) social meetings; (iii) ceremony, and (iv) formal meetings. Each type of learning event corresponded with different learning outcomes that arose from being involved in the partnership. Drawing from the literature on transformative and Indigenous learning, our study resulted in a synthetic “two-row” frame for cross-cultural learning and demonstrates that this learning was important for building cross-cultural collaborations for resource use.

Over the past decade, endoplasmic reticulum (ER) stress has emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. Cardiac therapy based on ER stress modulation is viewed as a promising avenue toward effective therapies for the diseased heart. Here, we tested whether sirtuin-1 (SIRT1), a NAD + -dependent deacetylase, participates in modulating ER stress response in the heart. Using cardiomyocytes and adult-inducible SIRT1 knockout mice, we demonstrate that SIRT1 inhibition or deficiency increases ER stress-induced cardiac injury, whereas activation of SIRT1 by the SIRT1-activating compound STAC-3 is protective. Analysis of the expression of markers of the three main branches of the unfolded protein response (i.e., PERK/eIF2 α , ATF6 and IRE1) showed that SIRT1 protects cardiomyocytes from ER stress-induced apoptosis by attenuating PERK/eIF2 α pathway activation. We also present evidence that SIRT1 physically interacts with and deacetylates eIF2 α . Mass spectrometry analysis identified lysines K141 and K143 as the acetylation sites on eIF2 α targeted by SIRT1. Furthermore, mutation of K143 to arginine to mimic eIF2 α deacetylation confers protection against ER stress-induced apoptosis. Collectively, our findings indicate that eIF2 α deacetylation on lysine K143 by SIRT1 is a novel regulatory mechanism for protecting cardiac cells from ER stress and suggest that activation of SIRT1 has potential as a therapeutic approach to protect the heart against ER stress-induced injury.

Clinical trials support the iterative advancement of modern medicine. However, challenges in achieving population-representativeness or participant sampling commensurate with the burden of disease can limit the generalizability and reproducibility of trial results. Here, we present the recruitment strategies and cohort profile of the Engaging Adolescents in Decisions about Return of Genomic Research Results non-randomized clinical trial (NCT0448106), where traditional, targeted hybrid, and digital recruitment methods were implemented with quota sampling to enroll diverse adolescents (ages 13–17) and young adults (ages 18–21). The largest proportion of participants enrolled through digital strategies (39.1%), followed by traditional (34.2%), and targeted hybrid strategies (23.2%). Despite lower enrollment, targeted hybrid recruitment, involving letters and text messages, had the largest proportion of participants from groups historically underrepresented in research (87.5%), compared to traditional (48.5%) and digital (32.3%) methods ( p  < 0.001). Our findings demonstrate a model for achieving both recruitment targets and inclusive trial participation to counteract overrepresentation of participants of European descent in clinical research.